Whom, How, and When Should We Screen for Barrett’s Esophagus?

Introduction

By Srinadh Komanduri, MD
Northwestern Memorial Hospital

There has been a significant shift in the management paradigm for Barrett’s esophagus (BE)–associated neoplasia over the past 10 years. We now have safe and effective endoscopic modalities (e.g., radiofrequency ablation, endoscopic mucosal resection) to treat dysplastic BE and early esophageal adenocarcinoma.

Despite these advances, the incidence of esophageal adenocarcinoma in the United States continues to rise. In addition, there are data to suggest that the majority of patients diagnosed with esophageal cancer do not have a preceding diagnosis of BE—only 15% of esophageal adenocarcinoma diagnoses occur during BE surveillance endoscopy.1-3

Current U.S. and international population-based guidelines do not advocate for universal endoscopic screening because it is not cost-effective. Endoscopic screening is reserved for patients with chronic gastroesophageal reflux and those who have potential clinical risk factors for esophageal adenocarcinoma (e.g., white race, obesity, family history of esophageal cancer). However, this strategy has been limited because many patients with heartburn never meet with a gastroenterologist for risk assessment.4

Proposed modalities for screening include unsedated endoscopy, transnasal office endoscopy, esophageal video capsule assessment, and the use of a cytologic sponge tethered to a string. There are promising early data for the less invasive cytologic sponge modality, but more evidence is needed prior to consideration of any of these tools for BE screening.

The time has come to embrace the concept of screening for BE, but the “whom,” “how,” and “when” remain unclear.

The Case for Screening for Barrett’s Esophagus

By Gary W. Falk, MD, MS
University of Pennsylvania Perelman School of Medicine

The incidence of esophageal adenocarcinoma continues to increase at a rate greater than that of any other cancer in the Western world. Survival for superficial adenocarcinoma (high-grade dysplasia and intramucosal cancer) is excellent, but the outcome for advanced-stage disease remains dismal. While BE is recognized to be the precursor lesion of this cancer, only approximately 5% of patients undergoing surgery for esophageal adenocarcinoma are known to have a prior diagnosis of BE. Furthermore, for patients with adenocarcinoma known to have BE, survival is improved and earlier-stage disease is typically discovered. Put another way, current endoscopic surveillance strategies for BE, while endorsed by professional societies around the world, have had a limited impact on the diagnosis and outcomes of esophageal adenocarcinoma.

An alternative approach would be to increase population screening for patients at risk for BE in an effort to find more individuals at risk for esophageal adenocarcinoma. While this goal is a noble one, the sheer number of patients with gastroesophageal reflux disease (GERD) and the cost of current screening, which is currently best handled by high-definition white light endoscopy, make this a cost-prohibitive approach. However, current practice guidelines, including the 2016 American College of Gastroenterology BE guidelines, do recommend targeted screening for BE in individuals at highest risk.1 This includes men with chronic or frequent reflux symptoms and two or more risk factors, including age older than 50, white race, central pattern obesity, current or past smoking history, and a confirmed family history of BE or esophageal adenocarcinoma. Although not ideal, especially because not all patients with esophageal adenocarcinoma have a history of GERD symptoms, this represents a practical approach until more scientifically rigorous and less costly approaches are developed. Alternatives such as capsule endoscopy have not worked out to date and unsedated transnasal endoscopy, while clearly accurate, has not gained traction at this time.

Other approaches are currently under study, including the noninvasive cytologic sponge. This method involves swallowing a tethered capsule which, upon entering the stomach, dissolves to reveal a sponge device that absorbs cells from the entire length of the esophagus as it is pulled back into the mouth and allows for the detection of BE with a sensitivity of 80% and specificity of 92%.2 Considerable resources are being allocated to the validation of this screening tool. Another novel inexpensive screening approach, especially promising in the era of electronic health records, is to develop a risk prediction tools score based on clinical features such as age, weight, GERD symptoms, smoking, and H. pylori status to identify patients at high risk for BE and apply current-generation screening to these individuals.3

The eventual ideal alternative to sedated high-definition white light endoscopy has not yet been identified. That being said, exciting new approaches are now undergoing study. These include the swallowed tethered reusable endomicroscopy capsule mentioned above, measurement of exhaled breath samples, oral microbiome swabs, and fecal molecular tests. As such, the future is bright for the development of novel, cost-effective screening techniques that will hopefully lessen the disease burden of esophageal adenocarcinoma.

Why We Should Not Screen for Barrett’s Esophagus

In order to effectively screen for a disease, several criteria need to be met. The disease in question should be a significant public health problem with substantial morbidity and mortality, have a precursor lesion that can be detected when asymptomatic, and be treatable with a potential cure when detected early. The test must be capable of detecting a high proportion of disease in the preclinical state, be safe to administer, reasonable in cost, lead to demonstrated improved health outcomes, and be widely applicable. While BE is a precursor for most esophageal adenocarcinomas, when we try to apply these criteria to screen for BE, we fall short in several areas at this time.

First, esophageal adenocarcinoma is a relatively uncommon cancer. While it has significant morbidity and mortality, the overall prevalence is small compared to other malignancies. It is estimated that in 2016 there will be 16,910 new cases of esophageal cancer in the United States (squamous cell and adenocarcinoma combined), compared to an estimated 134,490 new cases of colorectal cancer.1,2

Even though BE is the precursor for most esophageal adenocarcinomas, the risk of progression in patients with no dysplasia, who constitute the vast majority of cases (80%), is lower than previously estimated, at 0.1% to 0.3% per year. Indeed, in a recent meta-analysis of 7,930 patients with BE, there were only 88 deaths attributed to BE-related esophageal adenocarcinoma out of a total of 1,271 in that cohort.3 At the present time, other than histologic grade of dysplasia, there are no clinically applicable tools to further stratify risk and identify subsets of patients at a higher risk of disease progression. Patients with low- and high-grade dysplasia who are at higher risk of progression can be treated endoscopically, but constitute only a small minority of the overall BE population.

Endoscopic surveillance to detect progression to dysplasia or esophageal adenocarcinoma, as currently practiced, is limited by the following factors: well-documented variability in physician adherence to current guidelines on obtaining adequate biopsies during surveillance endoscopy, sampling error with random biopsy protocols (with surveillance sampling of only a small proportion of the BE mucosa) leading to missed dysplasia, and the relatively high rate of discordant interpretation of dysplasia grading between pathologists.

Another barrier to screening is the current lack of a widely applicable and acceptable tool for BE screening and a validated risk assessment score for BE risk. This tool would help in selecting the population at highest risk for developing BE and thus could benefit from screening. While we know that chronic and prolonged gastroesophageal reflux is the strongest risk factor for BE and esophageal adenocarcinoma, using only reflux symptoms to assess risk is inadequate since as many as 46% of patients with BE have no symptoms of chronic reflux.4 Other known risk factors include male sex, white race, central obesity, and increasing age. However, these characteristics do not narrow the population enough to justify applying the current screening techniques to all patients who fit this phenotype. Risk assessment tools are in development but have not been clinically validated yet.

Our currently available screening tools are not applicable for large-volume screening. The current screening method that is most widely available is standard white light sedated endoscopy with biopsy procurement. This approach is likely not cost-effective enough to be a reasonable screening tool, especially with the progression rate of BE to esophageal adenocarcinoma, which is lower than previously thought, and the high cost of this procedure. Unsedated transnasal endoscopy has been studied as a less expensive alternative endoscopy. While this can be done in the office without sedation, thus lowering costs, acceptability of this technique remains somewhat limited among patients and physicians despite studies showing comparable yield and participation rates reaching 50%.

While endoscopic means for screening have several limitations, a promising tool on the horizon is a sponge-on-a-string device. This device consists of a polyurethane sponge that is compressed within a gelatin capsule and connected to a string. The patient swallows the capsule, its shell dissolves, the sponge expands, and a nurse can pull the sponge out with the string through the patient’s mouth. The cells that are collected on the sponge can then be tested with biomarkers to detect BE. However, this tool is still in development and its overall acceptability and accuracy remains to be tested.

While esophageal adenocarcinoma is a lethal disease with a mostly asymptomatic precursor lesion in the form of BE, at the current time we fall short on several levels when it comes to screening. Hopefully, with ongoing research, many of the hurdles to effective screening will be overcome.